Psychiatry - November 2008 - (Page 34)

Table 7. AEs reported in memantine clinical trials (%)* PLACEBO ADVERSE EVENT n/a (n=922) Back pain Confusion Constipation Coughing Dizziness Dyspnea Fatigue Hallucinations Headache Hypertension Pain Somnolence Vomiting 2 5 3 3 5 1 1 2 3 2 1 2 2 MEMANTINE 20mg/day [95% CI] (n=940) 3 6 5 4 7 2 2 3 6 4 3 3 3 1.52 [0.84–2.75] 1.21 [0.81–1.81] 1.7 [1.05–2.75] 1.35 [0.82–2.22] 1.43 [0.97–2.11] 2.02 [0.91–4.47] 2.02 [0.91–4.47] 1.52 [0.84–2.75] 2.06 [1.30–3.28] 2.04 [1.16–3.59] 3.06 [1.45–6.48] 1.52 [0.84–2.75] 1.52 [0.84–2.75] 0.17 0.345 0.03 0.242 0.071 0.082 0.082 0.17 0.002 0.013 0.003 0.17 0.17 ODDS RATIO DISCUSSION ChEIs. Based on regulatory information from the package inserts of currently available AD therapies, several issues must be considered when optimizing treatment approaches. In general, cholinesterase inhibitors are associated with gastrointestinal side effects, particularly nausea, vomiting, and diarrhea. Across pivotal studies with donepezil, rivastigmine, and galantamine, fixed dose and forced titration have been shown to result in a higher frequency of gastrointestinal side effects, compared to studies employing a flexible-dose, flexibletitration design.25 Therefore, a flexible, tolerability-driven approach should be taken by physicians when increasing the dose of these medications. In clinical practice, at least one month of titration is often necessary before reaching the recommended, clinically beneficial dose, which is in accordance with the guidelines presented in the PI documents. In the case of galantamine and the rivastigmine oral formulation, taking the medication with a meal may decrease the likelihood of nausea or emesis. In addition, dosage adjustments of both donepezil and galantamine should be kept in mind when treating patients with hepatic impairment or those taking several medications at a time. Data available for the transdermal rivastigmine patch suggest that its tolerability and caregiver preference are superior to those of the orally administered drug,26–28 although it should also be noted that this formulation is the most recently introduced and the least studied of the anti-AD treatments. In addition, it should be mentioned that, due to their mechanism of action, all three ChEIs should be monitored for an exaggerated, succinylcholine-type muscle relaxation during anesthesia, vagotonic effects on sinoatrial and atrioventricular nodes (bradycardia or heart block), an increased gastric acid secretion, gastrointestinal bleeding, urinary obstruction, and seizures. ChEIs also have the P-VALUE *AEs (adverse events) reported in at least 2% of patients receiving 10–20mg/day memantine and at a higher frequency than placebo-treated patients; AEs with significant odds ratios (bold type) that occurred in >5% of patients are highlighted in gray. treated patients and at a rate greater than placebo, and no individual AE occurred at a frequency of five percent or more and twice the placebo rate. AEs reported in at least two percent of patients receiving up to 20mg/day memantine and at a higher frequency than placebo-treated patients are shown in Table 7. The statistically significant odds ratios of drug versus placebo are highlighted in gray. The memantine PI document notes that memantine dosage should be reduced in patients with severe 34 Psychiatry 2008 [ N O V E M B E R ] renal impairment. No dose adjustment is recommended for patients with mild to moderate hepatic impairment, but the drug should be administered with caution to patients with severe hepatic impairment. In addition, substances that alkalinize the urine (e.g., carbonic anhydrase inhibitors, sodium bicarbonate) could lead to a possible increase in AEs in patients taking memantine. The PI document for memantine does not indicate whether there are differential effects based on patients’ gender, age, or race.

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Psychiatry - November 2008 Editor's Message Editorial Advisory Board Contents PsychRx Letters to the Editor Measuring Adverse Events in Psychiatry Nonsuicidal Self Injury in Adolescents Relative Tolerability of Alzheimer's Disease Treatments Biracial Identity Development and Recommendations in Therapy Depression and Cardiovascular Disease: Just an Urban Legend? Three Risk Management Basics Journal Watch Classified Advertising Information for Authors

Psychiatry - November 2008

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